Therapeutic Peptides
First Claim
Patent Images
1. A substantially homogenous compound comprising a structure set out in Formula I,
[(X1)a—
- F1—
(X2)b]-(L1)c-WSPd
Formula Iwherein;
F1 is a vehicle;
X1 is selected fromP1-(L2)e—
P2-(L3)f-P1-(L2)e P3-(L4)g-P2-(L3)f-P1—
-(L2)e- andP4 (L5)h-P3-(L4)g-P2-(L3)f-P1-(L2)e-X2 is selected from;
-(L2)e-P1,-(L2)e-P1-(L3)f-P2,-(L2)e-P1-(L3)f-P2-(L4)g-P3, and-(L2)e-P1-(L3)f-P2-(L4)g-P3-(L5)h-P4 wherein P1, P2, P3, and P4 are each independently sequences of pharmacologically active peptides;
L1, L2, L3, L4, and L5 are each independently linkers;
a, b, c, e, f, g, and h are each independently 0 or 1,provided that at least one of a and b is 1;
d is at least 1; and
WSP is a water soluble polymer, the attachment of which is effected at any reactive moiety in F1;
said compound having a property of improved bioefficacy when administered in a multidose regimen.
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Abstract
The invention relates to compounds that exhibit improved bioefficacy in multidose administration. More specifically, the invention relates to polypeptides or peptides modified to include an antibody Fc region and one or more water soluble polymers.
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Citations
36 Claims
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1. A substantially homogenous compound comprising a structure set out in Formula I,
[(X1)a—- F1—
(X2)b]-(L1)c-WSPd
Formula Iwherein; F1 is a vehicle; X1 is selected from P1-(L2)e— P2-(L3)f-P1-(L2)e P3-(L4)g-P2-(L3)f-P1—
-(L2)e- andP4 (L5)h-P3-(L4)g-P2-(L3)f-P1-(L2)e- X2 is selected from; -(L2)e-P1, -(L2)e-P1-(L3)f-P2, -(L2)e-P1-(L3)f-P2-(L4)g-P3, and -(L2)e-P1-(L3)f-P2-(L4)g-P3-(L5)h-P4 wherein P1, P2, P3, and P4 are each independently sequences of pharmacologically active peptides; L1, L2, L3, L4, and L5 are each independently linkers; a, b, c, e, f, g, and h are each independently 0 or 1, provided that at least one of a and b is 1; d is at least 1; and WSP is a water soluble polymer, the attachment of which is effected at any reactive moiety in F1; said compound having a property of improved bioefficacy when administered in a multidose regimen. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 28, 29, 30, 31, 32, 33, 34, 35, 36)
wherein F1 is an Fc domain and is attached at the C-terminus of X1, and one or more WSP is attached to the Fc domain, optionally through linker L1;
- F1—
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5. The compound of claim 4 which is a multimer.
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6. The compound of claim 5 which is a dimer.
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7. The compound of claim 1 comprising a structure set out in Formula III
[F1—- X2]-(L1)c-WSPd
Formula IIIwherein F1 is an Fc domain and is attached at the N-terminus of X2, and one or more WSP is attached to the Fc domain, optionally through linker L1;
- X2]-(L1)c-WSPd
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8. The compound of claim 7 which is a multimer.
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9. The compound of claim 8 which is a dimer.
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10. The compound of claim 1 comprising a structure set out in Formula IV
[F1-(L2)e-P1]-(L1)c-WSPd-
Formula IVwherein F1 is an Fc domain and is attached at the N-terminus of -(L1)c-P1 and one or more WSP is attached to the Fc domain, optionally through linker L1.
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11. The compound of claim 10 which is a multimer.
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12. The compound of claim 11 which is a dimer.
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13. The compound of claim 1 comprising a structure set out in Formula V
[F1-(L2)e-P1-(L3)f-P2]-(L1)c-WSPd-
Formula Vwherein F1 is an Fc domain and is attached at the N-terminus of -L2-P1-L3-P2 and one or more WSP is attached to the Fc domain, optionally through linker L1.
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14. The compound of claim 10 which is a multimer.
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15. The compound of claim 11 which is a dimer.
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16. The compound of claim 1 wherein P1 and/or P2 are independently selected from a peptide set out in any one of Tables 4 through 20.
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17. The compound of claim 16 wherein P1 and/or P2 have the same amino acid sequence.
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18. The compound of claim 1 wherein F1 is an Fc domain.
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19. The compound of claim 1 wherein WSP is PEG.
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20. The compound of claim 1, wherein F1 is an Fc domain and WSP is PEG.
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21. The compound of claim 19 wherein PEG has a molecular weight of between about 2 kDa and 100 kDa.
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22. The compound of claim 21 wherein said PEG has a molecular weight of between about 6 kDa and 25 kDa.
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23. A composition comprising the compound of claim 19, wherein said composition comprises the PEGylated compound in an amount selected from the group consisting of:
- at least 50% PEGylated compound, at least 75% PEGylated compound, at least 85% PEGylated compound, at least 90% PEGylated compound, at least 95% PEGylated compound.
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28. A method of treating a disease or disorder comprising administering a composition comprising the compound of claim 1 in an amount effective to treat the disease or disorder.
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29. The method of claim 28, wherein said amount is from 0.1-1000 μ
- g/kg—
of body weight or from 0.1-150 μ
g/kg body weight.
- g/kg—
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30. A pharmaceutical composition comprising the compound of claim 1 in admixture with a pharmaceutically acceptable carrier thereof.
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31. A polynucleotide that encodes a compound comprising the structure selected from the group consisting of:
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(a) [(X1)a—
F1—
(X2)b]-(L1)c as defined in claim 1;(b) [X1—
F1]-(L1)c as defined in claim 4;(c) [F1—
X2]-(L1)c as defined in claim 7;(d) [F1-(L2)e-P1]-(L1)c as defined in claim 10; and (e) [F1-(L2)e-P1-(L3)f-P2]-(L1)c as defined in claim 13.
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32. A vector that comprises the polynucleotide of claim 31.
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33. A host cell that comprises the vector of claim 32.
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34. A method of producing a compound of claim 1 comprising growing the host cell of claim 33 in a suitable nutrient medium.
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35. The method of claim 34 further comprising isolating said compound from said cell or nutrient medium.
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36. The method of claim 34 or 35 further comprising pegylating said compound.
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24-27. -27. (canceled)
Specification